Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a practical animal model of pediatric AIDS. Intravenous inoculation of rhesus newborns with uncloned sivmac resulted in high virus load, no antiviral immune responses, severe immunodeficiency, and high mortality within three months. In contrast, immediate oral AZT treatment of SIV-inoculated rhesus newborns either prevented infection, or resulted in reduced virus load, enhanced antiviral immune responses, a low frequency of AZT-resistant virus isolates, and delayed disease progression with negligible toxicity. These results suggest that early chronic AZT treatment of HIV-exposed newborns will have benefits that clearly outweigh its potential side-effects.